Roles of SIRTI and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma a375-s2 cell death
Roles of SIRTI and phosphoinositide 3-OH kinase/protein kinase C pathways in evodiamine-induced human melanoma a375-s2 cell death
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DOI：
10.1254/jphs.fpj04055x
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发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Ikejima, T
中科院分区：
文献类型：
--
作者：
Wang, C;Wang, MW;Ikejima, T
我们以前证明，从吴茱萸（日本Goshuyu）中分离的吴茱萸碱在24小时内诱导人恶性黑色素瘤A375-S2细胞凋亡。本研究中，TUNEL法也表明吴茱萸碱诱导A375-S2细胞死亡的原因之一是细胞凋亡。在用吴茱萸碱处理指定的时间段后，抗凋亡蛋白SIRT 1的表达降低; p53的表达及其磷酸化均增强，而下游p21的瞬时诱导不足以促进细胞周期停滞。磷酸肌醇3-OH激酶（PI 3-K）/蛋白激酶C（PKC）生存途径的抑制以及随后对ERK级联的抑制可能有助于吴萸胺诱导的细胞死亡。此外，p53激活响应吴茱萸碱管理与PI 3-K/PKC促凋亡途径的激活，但不需要ERK的参与。在吴茱萸碱诱导的细胞死亡中，PI 3-K/PKC存活通路的抑制可能是SIRT 1失活和Bax/Bcl-2表达比例增加的原因。
We previously demonstrated that evodimine isolated from Evodia rutaecarpa (Goshuyu in Japan) induced apoptosis in human malignant melanoma A375-S2 cells within 24 h. In this study, TUNEL assay also indicated that one cause of A375-S2 cell death induced by evodiamine was apoptosis. After treatment with evodiamine for the indicated time periods, antiapoptotic protein SIRT1 expression was decreased; p53 expression and its phosphorylation were both enhanced, whereas transient induction of downstream p21 was not enough to promote cell cycle arrest. Inhibition of the phosphoinositide 3-OH kinase (PI3-K)/protein kinase C (PKC) survival pathway as well as subsequent inhibition of the ERK cascade might contribute to evodiamine-induced cell death. In addition, p53 activation in response to evodiamine administration was correlated with the activation of the PI3-K/PKC pro-apoptotic pathway, but did not require ERK participation. The inhibition of the PI3-K/PKC survival pathway might be responsible for SIRT1 inactivation and increased Bax/Bcl-2 expression ratio in evodiamine-induced cell death.